Advances in the understanding of the mechanisms of action of corticotropin releasing factor (CRF)/urocortins (Ucn), the stress hormones, and possible clinical indications resulted from the availability of refined tools that include the two CRF receptors (CRFRl and CRFR2) and their subtypes, antibodies to the different native ligands, and a number of synthetic analogs including receptor-selective agonists and antagonists. CRF, urocortins and their two receptors are widely distributed and affect the cardiovascular, gastrointestinal, immune, skin, reproductive, central nervous systems and metabolism where they play an important role in maintaining homeostasis. Chronic over-stimulation of these systems leads to diseases such as depression. Irritable Bowel Syndrome, psoriasis and many others. There is mounting evidence that the administration of CRFs' antagonists may ultimately alleviate symptoms in, or even cure, most diseases with stress-induced relapses. To test this hypothesis, safe, long acting and receptor-selective analogs need to be identified. Whereas we have designed long acting non-selective CRF antagonists (astressins), antagonists that are CRFR2-selecfive (astressin2-B) and CRFR1-selective agonists (stressini), we propose to complete our panoply of drug candidates with the design of a peptide CRFRl antagonist and a long acting CRFR2 agonist. We may reach this goal with the long standing complementary contributions of other members of the Program Project (Project 1 for in vitro bioassays, Project 3 for the determination of the structure of the interaction between receptor and ligands and Project 4 and outside collaborators for in vivo studies). The unusual gene processing of Ucn 2 and Ucn 3 may be clarified with the availability of synthetic N-terminally extended fragments in collaboration with Project 1.